The deposition of beta-amyloid (Abeta) in the Alzheimer's brain has long been regarded as a potential causative agent in the progression of Alzheimer's disease (AD) pathology. Over the past 10 years, characterization of the proteolytic events leading to Abeta generation has been the object of rigorous and exhaustive investigation. It is now understood that processing of the amyloid precursor protein (APR) by a group of enzymes known as the secretases ultimately underlies the liberation of AS. As more is known about these enzymes, it becomes increasingly clear that they likely have many substrates and inhibiting them may have multiple biological effects. The central question of this proposal is which intercellular signals regulate regulate the cleavage of APP. The processing of APP resembles that of other transmembrane proteins. The most notable among these is that which exists between APP and Notch. Binding of Notch to any of its cognate ligands (ie delta, jagged, serrate) results incleavage of the Notch receptor and shedding of the extracellular domain. This regulated step is followed by cleavage by through regulated intramembranous processing (RIP), leading to the liberation of the Notch Intracellular Domain (NICD). NICD is then translocated to the nucleus where it acts as regulator of transcription. With Notch, it is binding of ligand that activates the processing secretases. It appears likely that specific activation of APP cleavage may be induced by the binding of ligand to APP (and, perhaps ligand binding to heterologous receptors). The Specific Aims are as follows: 1) Determine the identity of ligands that bind APP and regulate cleavage in a manner consistent with Notch processing; 2) Determine the potential for growth-factor receptors to regulate cleavage of APP; 3) Elucidate the potential molecular pathways through which APP ligands or growth-factor receptors regulate APP cleavage; and, 4) Determine the levels and distribution of first messenger pathways (including APP ligands and heterologous receptors and their ligands) that regulate APP processing in control and Alzheimer tissue.